Phase 2 study of TAS-117, an allosteric akt inhibitor in advanced solid tumors harboring phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog gene mutations

Abstract

TAS-117 is a potent and selective allosteric pan-v-akt murine thymoma viral oncogene homolog (Akt) inhibitor. We conducted a single-arm single-center phase 2 study of TAS-117 in heavily treated patients with tumors refractory to systemic chemotherapy and harboring phosphatidylinositol 3-kinase (PI3K)/Akt mutations. Patients with gastrointestinal (GI) cancers were orally administered 16 mg TAS-117 daily, and those with non-GI tumors were administered 24 mg on a 4 days on/3 days off schedule. The primary endpoint was overall response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), PFS ratio, safety, and tolerability. Thirteen patients were enrolled: eight with non-GI (breast, ovarian, endometrial, and non-small cell lung) and five with GI (colon, rectal, gastric, and gallbladder) cancers. Ten patients were treated with TAS-117 after ≥ 4 lines of therapy. Twelve patients showed PIK3 catalytic subunit alpha (PIK3CA) mutations; one harbored an Akt1^E17K mutation. The median treatment duration was 1.4 months; the median number of treatment cycles was 2. The ORR was 8 %, and DCR was 23 %. The median PFS and OS were 1.4 and 4.8 months, respectively. Grade 3-4 treatment-related adverse events were anorexia (grade 3, 8 %) and hyperglycemia (grade 3, 8 %; grade 4, 8 %).Grade 3-4 treatment-related adverse events occurred in 27 % of grade 3 anorexia (9 %) and hyperglycemia (grade 3, 8 %; grade 4, 9\%). TAS-117 showed limited antitumor activity and manageable toxicity. Clinical efficacy was observed in patients with ovarian cancer harboring PIK3CA E545K mutations and in patients with breast cancer harboring PIK3CA H1047R and Akt1^E17K mutations.Trial registration: This study was retrospectively registered with ClinicalTrial.gov (NCT03017521 on January 11, 2017).

Keywords: Basket trial; PI3K/Akt mutations; Solid tumors; TAS-117.

Fig. 1

Waterfall plot depicting best percent changes in target tumor burden. All patients harbored PI3K aberrations, except for patients with breast cancer harboring AKT E17K* mutations. Two patients with clinical progression were excluded from this graph. Seven subjects did not undergo subsequent follow-up of tumor markers. Abbreviations: NSCLC, non-small cell lung cancer; NGG, next-generation sequencing; PI3K/Akt, phosphatidylinositol 3-kinase/protein kinase B; NA, not applicable (no follow-up of tumor markers for assessment)

Fig. 2

Swimmer plot depicting progression-free survival (PFS). All patients harbored PI3K aberrations, except for one patient with breast cancer harboring Akt E17K*. Abbreviations: RECIST, response evaluation criteria in solid tumors; NSCLC, non-small cell lung cancer; NGS, next-generation sequencing

Fig. 3

Analysis of progression-free survival (PFS) and overall survival (OS). (a) PFS 1 (prior to TAS-117), PFS 2 (TAS-117), and PFS 3 (after TAS − 117). (b) OS. Abbreviations: mPFS, median progression-free survival; OS, overall survival, CI, confidence interval; mo., months